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Blocked Autophagy Sensitizes Resistant Carcinoma Cells to Radiation Therapy

¹ Division of Radiobiology and Molecular Environmental Research, University of Tuebingen; ² Max-Planck Institute for Developmental Biology, Tuebingen, Germany; ³ Molecular OncoSurgery, Department of General Surgery, University of Heidelberg and German Cancer Research Center, Heidelberg, Germany; and ⁴ Department of Biochemistry, University of Lausanne, Epalinges, Switzerland

Requests for reprints: Ingrid Herr, University of Heidelberg and German Cancer Research Center-G403, Molecular OncoSurgery, Im Neuenheimer Feld 365, 69120 Heidelberg, Germany. Phone: 49-6221-56-38354; Fax: 49-6221-56-6119; E-mail: i.herr{at}dkfz.de.

Key Words: p53 • antisense control of gene expression • cell death and senescence • cellular, molecular, and tumor biology • radiation carcinogenesis

Autophagy or "self eating" is frequently activated in tumor cells treated with chemotherapy or irradiation. Whether autophagy represents a survival mechanism or rather contributes to cell death remains controversial. To address this issue, the role of autophagy in radiosensitive and radioresistant human cancer cell lines in response to -irradiation was examined. We found irradiation-induced accumulation of autophagosomes accompanied by strong mRNA induction of the autophagy-related genes beclin 1, atg3, atg4b, atg4c, atg5, and atg12 in each cell line. Transduction of specific target-siRNAs led to down-regulation of these genes for up to 8 days as shown by reverse transcription-PCR and Western blot analysis. Blockade of each autophagy-related gene was associated with strongly diminished accumulation of autophagosomes after irradiation. As shown by clonogenic survival, the majority of inhibited autophagy-related genes, each alone or combined, resulted in sensitization of resistant carcinoma cells to radiation, whereas untreated resistant cells but not sensitive cells survived better when autophagy was inhibited. Similarly, radiosensitization or the opposite was observed in different sensitive carcinoma cells and upon inhibition of different autophagy genes. Mutant p53 had no effect on accumulation of autophagosomes but slightly increased clonogenic survival, as expected, because mutated p53 protects cells by conferring resistance to apoptosis. In our system, short-time inhibition of autophagy along with radiotherapy lead to enhanced cytotoxicity of radiotherapy in resistant cancer cells. [Cancer Res 2008;68(5):1485–94]

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